Melatonin as an anti-aging therapeutic for the brain

The hormone melatonin, released by the pineal gland, plays a major role in determining the sleep cycle in humans. The molecule is also an activator of the immune system, exerts a potent anti-oxidant effect in cells, and — of great interest to biogerontologists — has long (though somewhat controversially) been implicated in the determination of lifespan. Recently, melatonin supplementation in rats was shown to slow age-related decline in the morphology and function of the skin (see our earlier posting, Melatonin, mitochondria, and dermal aging).

Melatonin has also been proposed as a potential therapeutic agent against age-related diseases of the brain, and even against brain aging per se. A detailed discussion of the relevant aspects of brain aging, along with a summary of studies demonstrating a beneficial effect of the compound on animal models neurological diseases such as Parkinson’s and Alzheimer’s, can be found in a recent review by Bondy and Sharman at UC-Irvine:

The events associated with brain aging are enumerated with emphasis on increased oxidative and inflammatory processes and on mitochondrial dysfunction. Several of these factors are further increased in a wide range of overt age-related neurological diseases. This generality has given impetus to concepts concerning similar therapeutic approaches common to a series of neurodegenerative disorders. Animal and cell culture models of several such disorders have benefited from the application of melatonin. The mechanisms underlying the neuroprotective properties of melatonin are likely to involve activation of specific melatonin receptors. This can lead to modulation of transcription factors and consequent altered gene expression, resulting in enhancement of antioxidant enzymes and downregulation of basal levels of inflammation. Melatonin has potential utility both in slowing normal brain aging and in treatment of neurodegenerative conditions. This is reinforced by the low cost of melatonin and its very low toxic hazard.

The manuscript reviews the evidence for oxidative damage as a prominent feature of aging in the brain, address the evidence that inflammation plays a contributory role in age-related decline of the CNS, and describe the age-associated onset of mitochondrial dysfunction — which is itself caused by, and a further cause of, oxidative damage.

Despite the significance of oxidation in brain aging and neurodegeneration, the authors warn against the use of antioxidants as therapeutics, for two reasons: First, many anti-oxidants (such as vitamin E) are simply poorly bioavailable to the CNS, taking months of heavy supplementation before equilibrium is reached. Second, many processes in the brain rely on oxidative molecules for signaling; hence broad-spectrum antibiotics might interfere with specific pathways and therefore have deleterious side effects.

Melatonin appears to escape both criticisms. The molecule is highly bioavailable to the CNS following oral administration. Furthermore, while it is (chemically speaking) a potent antioxidant, it is present at concentrations far lower than many dietary antioxidants — picomolar opposed to high micromolar or millimolar. For that matter, its levels are far lower than those of the oxidative species against which we might hope for protection. It is thought to exert its antioxidant effects indirectly, via induction of anti-oxidant proteins that catalytically convert free radicals and reactive oxygen species (ROS) into harmless water (and, as a bonus, have probably been evolutionarily selected not to interfere in cellular signaling pathways). Thus, by activating cellular defenses, melatonin can ameliorate oxidative damage far beyond its capacity as a molecular radical scavenger.

Whether via its effects on oxidation, mitochondrial function or inflammation, melatonin has been shown to improve outcomes in animal models of neurological disease. (If you’re able to access the paper, the table summarizing the results is here).

Melatonin’s effect on gene transcription is mediated by specific receptors, of which the human genome contains two (MT1/MTNR1A and MT2/MTNR1B). Interestingly, the FDA recently approved a melatonin receptor agonist for use as a sleep aid. The drug, ramelteon, is marketed as Rozerem (via an incomprehensible campaign involving Abraham Lincoln and a beaver).

Intriguing possibility: If melatonin exerts its effects against brain aging via these receptors, it means that a pharmaceutical with potential as an anti-aging therapeutic has already been subjected to trials and approved for daily use. (Can you say “off-label prescription“?)

I’ve just found your blog and I’m a happy man. I’m just about to complete my Ph.D in Biochemistry (Aging Muscle Metabolism). I’ve (35 years old) been taking melatonin (5mg time release/night) for quiet some time now. Additionally I have recommended it to many of my guinea pigs/friends & family. I’ve read many papers and have not really come across any significant negatives. I am very curious about one thing though and was wandering whether you may have come across something in your readings.

Have you read any reports of melatonin receptor down regulation or desensitization with chronic use?

Department and Clinic of Geriatrics, Medical College in Bydgoszcz, N. Copernicus University of Torun, Bydgoszcz, Poland.

The disturbances in pro- and antioxidant balance may play an important role in the pathomechanism of aging. The pineal hormone melatonin, which exerts effective antioxidative properties, is suggested to be involved in the aging process. The aim of this study was to compare the oxidative stress in erythrocytes of healthy young adults and elderly people, and to determine the influence of melatonin supplementation on measured parameters in both examined groups. The malondialdehyde (MDA) and reduced glutathione levels as well as Cu-Zn superoxide dismutase (SOD-1), catalase, glutathione peroxidase (GSH-Px), glutathione S-transferase (GST) and glutathione reductase (GR) activities in erythrocytes and morning serum melatonin concentration in 14 healthy young adults and 14 healthy elderly people at baseline and after the 30th day of melatonin (5 mg daily) supplementation were determined. A significant age effect on increasing the MDA level and decreasing SOD-1, GSH-Px and GR activities as well as melatonin concentration was observed. Melatonin supplementation resulted in a significant increase in melatonin concentration, SOD-1 and GR activities and a decrease in the MDA level in both examined groups. These data indicate an age-related augmentation of oxidative stress in erythrocytes and the improvement of erythrocytic antioxidative defense by melatonin administration. These results might suggest melatonin supplementation to prevent age-related diseases and to prolong the lifespan and improve the quality of life of elderly people.